Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway

Abstract

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa.

Growth Inhibitory Effect of Wedelolactone in Combination with Cisplatin on PA-1 Ovarian Cancer Cell Line

“…Considerable drawbacks involved in "chemotherapy treatment" are the serious toxicity and drug resistance. Numerous studies have affirmed that natural compounds with chemo preventive property could improve the ovarian cancer response rate in combination with chemotherapeutic agents both in vitro and in vivo [26][27][28][29] . Though Wedelolactone presents limited bioavailability, low doses of physiologically practicable concentrations are appropriate for its chemotherapeutic effect.…”

Chitosan Oligosaccharide Promotes Junction Barrier through Modulation of PI3K/AKT and ERK Signaling Intricate Interplay in T84 Cells

“…AMPK is activated by phosphorylation of AMPK-α subunit at threonine-172 in response to growth factors (GF) through Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ) and is essential for GF-mediated AKT activation and biological functions [ 36 , 37 , 38 ]. Previously, we and others have reported that compound C, an AMPK inhibitor, inhibits the activation of AKT indicating that AMPK is an important regulator of AKT pathway [ 17 , 39 ]. Moreover, AKT is also activated by direct activation of epidermal growth factor receptor (EGFr) [ 40 ].…”

Knockdown of ARHGAP30 inhibits ovarian cancer cell proliferation, migration, and invasiveness by suppressing the PI3K/AKT/mTOR signaling pathway

“… 28 Compound C passed PI3K/AKT/mTOR/NF- κB pathway has been shown to inhibit OC progression. 15 Furthermore, CXCR4 has been shown to modulate PI3K/Akt/mTOR signaling in epithelial OC (EOC). In addition, the CXCR4-PI3K/Akt/mTOR axis promotes the formation of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), resulting in resistance to chemotherapy.…”

“… 14 Inhibitors of the PI3K/AKT/mTOR pathway have been shown to dramatically slow the growth of OC. 15 In roughly 70% of OC cases the PI3K/AKT/mTOR pathway is upregulated, which results in increased angiogenesis, cell survival, and metabolism. 16 Several clinical studies have shown that the PI3K pathway is a promising target for the treatment of OC.…”